Bulk RNA sequencing of total lung cells from Atg14f/f and Atg14f/f-LysM-cre mice.

Host responses to infection are determined by how well primed the innate immune system is to respond on first exposure to an invader. Here, we describe innate immune priming prior to infection that conferred resistance to respiratory pathogens. The lung innate immune priming for early response to infection occurred via functional reprogramming of innate immune cells independently of either the microbiome or adaptive immunity. In normal animals, priming was suppressed by autophagy in alveolar macrophages, rendering animals susceptible to infection. Mice lacking autophagy in myeloid cells demonstrated swifter and more efficient innate immune clearance of Staphylococcus aureus infection while minimizing lung damage and inflammation. Enhancing the primed state of innate immunity by blocking autophagy also protected against influenza A virus. Inhibition of autophagy primed innate immunity in the lung by triggering elevated IL-1α expression in autophagy-deficient alveolar macrophages, which enhanced IL-1R/MyD88 signaling in neutrophils. Transiently introducing IL-1α or inhibiting autophagy conferred broad spectrum protection in mice against bacterial and viral pathogens. Ultimately, parallel to trained innate immunity induced by prior microbial exposure, priming of innate immunity by inhibition of autophagy is a robust and broad spectrum resistance mechanism, providing an attractive strategy to fine-tuning immune responses to combat important respiratory infections